Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][C@@H:56]([N:58]2[CH2:63][CH2:62][C@H:61]([OH:64])[C@@H:60]([CH3:65])[CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][C@H:61]1[CH2:62][CH2:63][N:58]([C@@H:56]([CH3:55])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:59][C@@H:60]1[CH3:65]
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 56 analogously to the method described in example 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH2:3][CH2:2]1.[CH3:17][C:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[CH3:17][C:18]1[N:19]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30]3[N:31]=[C:8]([CH2:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:10]4[CH2:11][O:12][CH2:13][CH2:14][C:15]=4[N:32]=3)=[CH:27][CH:28]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCOCC1C(=O)CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)COCC3)cc1
Temperature: 50 °C
Yield: 4.2 %

Procedure:
3-(2-(Tetrahydro-2H-pyran-4-yl)acetyl)dihydro-2H-pyran-4(3H)-one (200 mg, 0.88 mmol), 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (190 mg, 0.88 mmol, Example 41c) and potassium carbonate (122 mg, 0.88 mmol) was slurrified in EtOH (4 mL) and heated to 50° C. for 15 h. DCM and water were added. The organic phase was separated, dried with MgSO4 and the solvent was evaporated. The crude product was purified using preparative HPLC yielding N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (15.0 mg, 4.0%).
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][Br:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br-:14].[Br:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][P+:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:18]=1
Reactant: CCCCP(CCCC)CCCC
Reactant: BrCc1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1ccc(CBr)cc1
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture of tri-n-butylphosphine (5.7 g, 28.4 mmol) in toluene (50 mL) was added dropwise to a mixture of α,α'-dibromo-p-xylene (15 g, 56.8 mmol, 2 eq.) in 200 mL of toluene under argon gas. The reaction mixture was allowed to stir for several days at room temperature under argon, after which time the tri-n-butylphosphonium bromide salt had crystallized out of solution. The crystals were filtered and washed three times each with 50 mL portions toluene and hexanes, then air dried: 1H NMR (CDCl3) δ 0.93 (t, 9H), 1.45 (m, 12H), 2.40 (m, 6H), 4.33-4.37 (d, 2H), 4.47 (s, 2H), 7.37-7.40 (d, 2H), 7.46-7.49 (dd, 2H).
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:8]3[CH2:7][CH2:6][CH:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CCC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 85.5 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-sec-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol) and 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 152 mg of the desired product as a white solid (50%). ESI-MS: 339 (M−16)+. 1H NMR (400 MHz, DMSO-d6) δ=8.30 (s, 1H), 7.88 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.56 (m, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.12 (dd, J=2.3, 8.8 Hz, 1H), 4.70 (d, J=5.8 Hz, 1H), 4.40-4.28 (m, 1H), 3.55-3.41 (m, 2H), 2.26-1.07 (m, 12H), 0.94-0.79 (m, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(CC)CC.[CH2:17]=[O:18].Cl>CC#N>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH:17]=[O:18]
Reactant: Oc1cc(F)cc(F)c1
Reactant: C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of commercially available 3,5-difluorophenol (3.000 g; 23.10 mmol), anh. magnesium chloride MgCl2 (6.587 g; 69.20 mmol), and NEt3 (8.04 ml; 57.70 mmol) in anh. MeCN (100 ml) was stirred at rt, under nitrogen, for 20 min. Paraformaldehyde (3.459 g; 115.00 mmol) was then added, and the resulting mixture was heated to 80° C., under nitrogen, for 1.5 h. After cooling to rt, aq. 1N HCl (80 ml) was added, and the aq. layer was extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2,4-difluoro-6-hydroxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.67 min.; no ionisation.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:26][CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=2)[C:28]1=[O:39].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:38][O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:39])[CH:27]([NH:26][C:16]([C:10]1[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=1[C:12]([F:13])([F:14])[F:15])=[O:18])[CH2:36][CH2:35]2
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: COc1ccc2c(c1)CCC(N)C2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 300 mg, 1.167 mmol) in dichloromethane (4 mL) at 0° C. was added oxalyl chloride (0.204 mL, 2.333 mmol) and a few drops of N,N-dimethylformamide, and the mixture was stirred at the same temperature for 20 min. Next, the reaction mixture was stirred for 5 min at room temperature, and the solvent and excess oxalyl chloride were evaporated off. The residue was dissolved in anhydrous dichloromethane and evaporated to give an oily residue which became solid upon drying under vacuum. The solid material was dissolved in 5 mL of dichloromethane and 2-amino-6-methoxy-3,4-dihydronaphthalen-1(2H)-one hydrochloride (223 mg, 1.167 mmol, J. Heterocyclic Chem., 29:1245 (1992)), diisopropylethylamine (0.61 mL, 3.50 mmol), and 4-(dimethylamino)pyridine (7.13 mg, 0.058 mmol) were added. The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate, washed with 1N HCl, saturated sodium bicarbonate and brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to give a dark green solid residue. The product was crystallized from ethyl acetate and hexane to give 317 mg of the desired N-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide. The mother liquor was purified by Combiflash (40 g silica gel) eluting with 2:8 ethyl acetate-hexane to give additional 119 mg of the product (87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, d, J=8.80 Hz), 7.82 (1H, br. s.), 7.61 (2H, d, J=6.82 Hz), 7.47-7.58 (3H, m), 6.89 (1H, dd, J=8.80, 2.42 Hz), 6.75 (1H, d, J=2.20 Hz), 4.77 (1H, ddd, J=13.31, 4.84, 4.73 Hz), 3.90 (3H, s), 3.23-3.36 (1H, m), 3.02-3.10 (1H, m), 2.94-3.02 (1H, m), 1.96-2.10 (1H, m).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14]OC(N[C@H](C(O)=O)CC3C=CC=CC=3C)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:14]=[C:12]1[C:13]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1ccccc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=C1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes and then the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying there were obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].CCCCCC>O1CCCC1.[Cu]I>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(I)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CSc1nccc(C#C[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
4-Iodo-2-(methylsulfanyl)pyrimidine (2.0 g, 8.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). To this solution was added triethylamine (1.4 mL, 10.1 mmol), copper (I) iodide (80 mg, 0.4 mmol) and dichlorobis(triphenylphosphine) palladium (II) (140 mg, 0.24 mmol). (Trimethylsilyl)acetylene (1.4 mL, 10.1 mmol) was added dropwise to the resulting solution. After the addition of (trimethylsilyl)acetylene was complete the reaction was stirred at room temperature for 2 hours. Hexane was added to the reaction mixture and the mixture was filtered to remove precipitates. The solution was concentrated to give a syrup, that was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 1.76 g (99%) of 2-(methylsulfanyl)-4-[(trimethylsilyl)ethynyl]pyrimidine. 2-(Methylsulfanyl)-4-[(trimethylsilyl)ethynyl]pyrimidine (1.76 g, 8.0 mmol) was dissolved in methanol (60 mL). To this solution was added potassium fluoride (467 mg, 8.0 mmol) and the resulting mixture stirred at room temperature for 5 minutes. The solution was concentrated and ethyl acetate and water were added. The phases were separated and the aqueous phase extracted with additional ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated to give 1.0 g (83%) of 4-ethynyl-2-(methylsulfanyl)pyrimidine as a white solid. 1H NMR (CDCl3): δ 8.51 (d, 1H), 7.06 (d, 1H), 3.34 (s, 1H), 2.56 (s, 3H); MS m/z 151 (M+1).
Reaction SMILES: [C:1]1(=[O:18])[N:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[C:19]([C:24](=[CH:30]OCC)[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])[CH2:20][CH2:21][CH3:22]>CCOCC>[C:19]([C:24](=[CH:30][NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N:5]1[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]2[C:1]1=[O:18])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Solvent: CCOCC
Product: CCCC(=O)C(=CNc1ccccc1N1C(=O)c2ccccc2C1=O)C(=O)OCC

Procedure:
2-Phthalimidoaniline (44.0 g, 0.21 moles) and ethyl 2-butyryl-3-ethoxyacrylate (45 g, 0.21 moles) were heated together in fusion for 10 minutes then allowed to cool, forming a tan solid. The ethyl 2-buryryl-3-(2-phthalimidophenylamino)acrylate (83.0 g, 97%) was stirred in ether, filtered and dried under vacuum, m.p 153°-5° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[C:28]([O:35][CH3:36])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.[NH4+].[OH-].O>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[C:28]([O:35][CH3:36])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: COc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)ccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (141 mg, 281 μmol) in dichloromethane (4.3 mL) was added trifluoroacetic acid (641 mg, 433 μL, 5.62 mmol) and the mixture stirred at room temperature for 16 h. The mixture was diluted with 25% aqueous NH4OH, dichloromethane, and water. The organic phase was separated and washed with water (2×), then concentrated in vacuo and purified by chromatography (silica, 3 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (35 mg, 87 μmol, 31%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H), 8.37 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 4.05 (br. s, 1H), 3.81 (d, J=11.9 Hz, 1H), 3.67 (dd, J=10.9, 3.5 Hz, 1H), 3.49 (dd, J=11.1. 1.9 Hz, 1H), 3.37 (m, 2H), 3.08 (m, 1H), 2.97 (s, 1H), 1.81 (m, 1H), 1.65 (m, 1H), 1.16 (d, J=6.8 Hz, 6H); MS (EI/CI) m/z: 402.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=N\C(=O)C)/[N:6]([CH:8]([F:10])[F:9])[CH:7]=1.[OH:15]S([O-])(=O)=O.[K+]>CC#N.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)([O-])O
Reactant: CC(=O)/N=c1\ccc(Br)cn1C(F)F
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1ccc(Br)cn1C(F)F
Yield: 52 %

Procedure:
To a stirred solution of the crude N-[5-Bromo-1-difluoromethyl-1H-pyridin-(2E)-ylidene]-acetamide (1 g) in 10 ml CH3CN was added 1% KHSO4 in water (10 ml). The reaction mixture was heated at reflux for 3 hrs. The reaction mixture was cooled down and the solvent was removed under reduced pressure. Without any workup this crude was purified by column chromatography using 10% ethyl acetate in hexane to get 5-Bromo-1-difluoromethyl-1H-pyridin-2-one (550 mg, 52%).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]#[N:7])[CH3:2].C([Li])CCC.[C:13]1([CH2:23][CH2:24][CH2:25]I)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>O1CCCC1>[CH2:1]([O:3][CH:4]=[C:5]([C:6]#[N:7])[CH2:25][CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC=CC#N
Reactant: ICCCc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC=C(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 1.5 mL (0.014 mole) of 3-ethoxyacrylonitrile in 45 mL of tetrahydrofuran was cooled to about -110° C., and 6.2 mL (0.015 mole) of 2.5M n- butyllithium in hexanes was added dropwise at a rate to keep the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was stirred for about ten minutes, and then a solution of 4.0 grams (0.014 mole) of 3-(naphth-1-yl)propyl iodide in 15 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at about -78° C. for two hours. After this time the reaction mixture was allowed to warm to ambient temperature as it stirred for about 16 hours. The reaction mixture was concentrated under reduced pressure, yielding a dark residual oil. The oil was passed through a short column of silica gel using methylene chloride as the eluant. The eluate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 2:1 methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.0 gram of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3C=CC=[CH:19][C:14]=3[N:13](C)[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.CO[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]2[O:34][CH2:33]2)=[CH:26][CH:25]=1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:13]([CH:14]([CH3:15])[CH3:19])[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[O:34]1[CH:32]([CH2:31][O:30][C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)[CH2:33]1
Reactant: Cn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: COc1ccc(OCC2CO2)cc1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and glycidyl 4-methoxyphenyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl.Cl.O1CCOCC1>CO>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:6][CH:7]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: C1COCCN1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCCl)cc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCN4CCOCC4)cc3)cc12
Yield: 69.6 %

Procedure:
In a 10 mL microwave vial 6-(4-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70.0 mg, 0.179 mmol) and morpholine (0.155 ml, 1.791 mmol) were added in methanol (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 30 min. The volatiles were evaporated in vacuo. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:2 to 0:1). The product was obtained as the parent and converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallized from EtOH-H2O to give 55 mg of N-methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine as a yellow powder (60% yield), LCMS m/z=442 (M+1) (Method D) (retention time=1.12 min). 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H), 9.63 (s, 1H), 9.10-8.79 (m, 3H), 8.34 (d, J=8.2 Hz, 1H), 8.28-8.12 (m, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 4.60-4.46 (m, 2H), 4.06-3.91 (m, 2H), 3.91-3.74 (m, 2H), 3.67-3.41 (m, 4H), 3.38-3.09 (m, J=10.1 Hz, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1N=CN(C([N:31]2[CH:35]=[N:34]C=C2)=O)C=1.C(OCC)(=O)C>O>[C:17]1([C:35]2[N:34]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g) and toluene (50 mL) was added CDI (3.9 g), followed by stirring at room temperature for 3 hours. Then, N′-hydroxybenzenecarboxyimidate (3.3 g) was added thereto, followed by stirring for 1.5 hours and then heating and refluxing for 2 hours. After leaving to be cooled, to the reaction liquid were added ethyl acetate and water, and the organic phase was separated. The organic phase was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue were added hexane and ethyl acetate, and the resulting solid was collected by filtration to obtain tert-butyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (5.46 g).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[S:20]([NH2:24])([NH2:23])(=[O:22])=[O:21].O>COCCO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:23][S:20]([NH2:24])(=[O:22])=[O:21])=[CH:14][CH:13]=1
Reactant: NS(N)(=O)=O
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Solvent: O
Solvent: COCCO
Product: NC(N)=Nc1nc(-c2nc(N)ccc2C=NS(N)(=O)=O)cs1
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (2.1 g) and sulfamide (2.9 g) in 2-methoxyethanol (10.5 ml) was stirred for 3 hours at 70°-75° C. The mixture was added to water, isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(aminosulfonylimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.28 g).